4-isoavenaciolide covalently binds and inhibits VHR, a dual-specificity phosphatase.

Abstract:

:A potent inhibitor of a dual-specificity protein phosphatase, VHR (vaccinia H1 related), was isolated during a screening of microbial metabolites. This inhibitor was identified as 4-isoavenaciolide (4-iA), and was determined to irreversibly inhibit VHR phosphatase activity with a 50% inhibitory concentration of 1.2 microM. Detailed tandem mass spectrometry analyses of proteolysed fragments revealed that two molecules of 4-iA bound a molecule of VHR at the two different fragments: one containing the catalytic domain and the other containing the alpha6 helix positioned surface domain. As 4-iA possesses a reactive exo-methylene moiety, it is possible that 4-iA inhibits VHR through the direct binding to the cysteine residue in the catalytic site (Cys124). Furthermore, 4-iA inhibited dual-specificity protein phosphatases and tyrosine phosphatases, but did not inhibit serine/threonine phosphatases. These results suggest that 4-iA is a cysteine-targeting inhibitor of protein phosphatases with a common HCX5RS/T motif in the catalytic site.

journal_name

FEBS Lett

journal_title

FEBS letters

authors

Ueda K,Usui T,Nakayama H,Ueki M,Takio K,Ubukata M,Osada H

doi

10.1016/s0014-5793(02)03065-x

keywords:

subject

Has Abstract

pub_date

2002-08-14 00:00:00

pages

48-52

issue

1-3

eissn

0014-5793

issn

1873-3468

pii

S001457930203065X

journal_volume

525

pub_type

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